The long-term project goal is to provide the evidence-base for the development of sustainable strategies to further reduce malaria transmission in southern Africa and assess the feasibility of malaria elimination through an integrated understanding of local malaria epidemiology, vector biology, parasite population structure and community and household-level beliefs and actions. Building upon the Johns Hopkins Malaria Research Institute field site in Choma District in rural southern Zambia as a regional center of excellence in malaria research, we propose to investigate the changing epidemiology of malaria in three distinct transmission settings in southern Africa reflecting different stages of malaria control (successful - Choma, ineffective - Nchelenge, resurgent - Mutasa) through prospective hospital, clinic and community-based studies to address the following: Aim 1) Measure changes in spatio-temporal patterns of malaria parasitemia in three distinct epidemiological settings in southern Africa and identify individual, household and ecological risk factors for symptomatic and asymptomatic parasitemia in each setting; Aim 2) Identify individual, household and ecological risk factors for gametocyte carriage during high and low transmission seasons in three distinct epidemiological settings in southern Africa; Aim 3) Measure spatio-temporal changes in age specific antibody responses to Plasmodium falciparium antigens using sero-epidemiological surveys in the three regions of southern Africa; Aim 4) Identify targeted, risk-based combinations of malaria control strategies that are cost-effective and acceptable to the community using mathematical modeling approaches to optimize decision algorithms based on locally available survey and surveillance data. Detailed understanding of malaria transmission dynamics in three different epidemiological settings will thus inform the development of locally-adapted, cost-effective and community-supported strategies for malaria control. These epidemiological investigations will be closely linked with studies of spatio-temporal changes in the anopheline vector and Plasmodium population structure in response to ecological changes and malaria control efforts. This integrated, evidence-based approach to malaria control will form the foundation for a regional center of excellence for malaria research in southern Africa and the foundation for regional malaria elimination.